Abstract
Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes.Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system.
Highlights
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat mild-to-moderate pain in rheumatoid and osteoarthritis as well as musculoskeletal injuries [1, 2]
Total bilirubin and serum glucose was dose dependently reduced, and the observed hypoglycemia may be linked to altered ion channel activity of insulin secreting beta cells as was demonstrated for several NSAIDs [27]
The changes may be related to the weight loss and mild kidney injury serum creatinine was basically unchanged or even reduced at high dose regimen
Summary
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat mild-to-moderate pain in rheumatoid and osteoarthritis as well as musculoskeletal injuries [1, 2]. > 1000 tons of diclofenac are produced in the form of capsules, tablets, ointments and intravenous solution, underlining its extensive use www.impactjournals.com/oncotarget [3, 4]. This NSAID exerts anti-inflammatory, analgesic and anti-pyretic effects through different mechanisms [5]. It inhibits cyclooxygenase 1 and 2 at an IC50 of 0.076 and 0.026μM, respectively and modulates arachidonic acid metabolism and its pool size [6]. Diclofenac inhibits activity of the neuropeptide substance P and is a partial agonist of the peroxisome proliferator activated receptor gamma (PPARγ) [8]
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